This study will develop an efficient and flexible synthetic route to the polyene macrolide antibiotic class of compounds. With this in mind, the immediate goal will be the total synthesis of amphotericin B, the only compound of this class for which the stereochemistry is known. The synthetic strategy incorporates the use of readily available amino acids as chiral, versatile starting materials. In addition, this study will explore the possibilities for acyclic stereoselection mediated by intramolecular chelation. The polyene macrolide antibiotics are potent antifungal agents and are clinically important in the treatment of human mycoses. However, their toxicity presents the use of these drugs in many instances when they would be most beneficial. Therefore, a longer term goal of these studies is to develop an ergosterol-specific polyene antibiotic which holds promise of extremely low toxicity while retaining the desired antifungal properties. This will be accomplished through structural correlation of amphotericin B with other polyene macrolide antibiotics and synthetic modification.
| Hartsel, S C; Perkins, W R; McGarvey, G J et al. (1988) A selective cholesterol-dependent induction of H+/OH- currents in phospholipid vesicles by amphotericin B. Biochemistry 27:2656-60 |
